PROJECT SUMMARY ! Despite the advances in understanding human aging and aging-associated cognitive decline, molecular and cellular mechanisms underlying aging associated impairments in learning and memory are poorly understood. Others and we published that individual neurons age differently. This observation suggests that synapses might also undergo differential aging. Very little is known about the molecular mechanisms underlying synaptic aging and how synaptic aging results in aging associated memory deficits. To address this, we will study the aging associated changes in the postsynaptic L7 motor neuron (L7MN) of Aplysia whose normal functioning are critical for the learning of gill withdrawal reflex (GWR). Along with us, others have used Aplysia as a model to understand aging associated changes in neuronal physiology, response to neurotransmitters, gene expression and behavioral learning. In a study that examined electrophysiological and gene expression changes in identified neuron R15 of Aplysia, we recently described specific changes in burst firing and action potentials in R15 during aging. We also described aging associated changes in the expression of several genes in R15 and specific changes in expression of key regulators of transcription and translation in four identified neurons (L7, L11, R2, R15) of Aplysia. The central hypothesis of this proposal developed from our own published data and preliminary results is that specific changes in plasticity at sensory to motor neuron synapses results in impairments in GWR learning during aging. To test this hypothesis, we will measure synaptic and transcriptomic changes in L7MN following two different learning assays (sensitization and habituation) carried out at three stages of aging: sexually mature, late, and senescence (~6, 9 and 12 months respectively). Successful completion of these studies will identify new critical regulators of neuronal aging, plasticity and memory storage. Furthermore, we anticipate that these studies will facilitate the identification of new candidates for therapeutics development for aging associated cognitive decline.!